He Pei, Yu Huiguang, Deng Xiaofei, Xin Lilan, Xu Bin, Zhou Hai-Bing, Dong Chune
Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; State Key Laboratory of Virology, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatiorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430071, China.
Eur J Med Chem. 2024 Mar 15;268:116236. doi: 10.1016/j.ejmech.2024.116236. Epub 2024 Feb 13.
Estrogen receptor (ER) β and histone deacetylases (HDACs), when overexpressed, are associated closely with the occurrence and development of prostate cancer and are, therefore, considered important targets and biomarkers used in the clinical treatment of prostate cancer. The present study involved the design and synthesis of the first ERβ and HDAC dual-target near-infrared fluorescent probe with both imaging capacity and antitumor activity for prostate cancer. Both P1 and P2 probes exhibited excellent ERβ selectivity, with P1 being almost exclusively selective for ERβ compared to ERα. In addition, P1 exhibited good optical properties, such as strong near-infrared emission, large Stokes shift, and better anti-interference ability, along with excellent imaging ability for living cells. P1 also exhibited potent inhibitory activity against HDAC6 and DU-145 cells, with IC values of 52 nM and 0.96 μM, respectively. Further, P1 was applied successfully for the in vivo imaging of prostate cancer in a mouse model, and significant in vivo antitumor efficacy was achieved. The developed dual-target NIR fluorescent probe is expected to serve as an effective tool in the research on prostate cancer, leading to novel insights for the theranostic study of diseases related to ERβ and HDACs.
雌激素受体（ER）β和组蛋白去乙酰化酶（HDACs）在过表达时与前列腺癌的发生和发展密切相关，因此被认为是前列腺癌临床治疗中的重要靶点和生物标志物。本研究涉及设计和合成首个具有成像能力和前列腺癌抗肿瘤活性的ERβ和HDAC双靶点近红外荧光探针。P1和P2探针均表现出优异的ERβ选择性，与ERα相比，P1几乎对ERβ具有唯一选择性。此外，P1表现出良好的光学性质，如强近红外发射、大斯托克斯位移和更好的抗干扰能力，以及对活细胞的优异成像能力。P1对HDAC6和DU-145细胞也表现出强效抑制活性，IC值分别为52 nM和0.96 μM。此外，P1成功应用于小鼠模型中前列腺癌的体内成像，并实现了显著的体内抗肿瘤疗效。所开发的双靶点近红外荧光探针有望成为前列腺癌研究的有效工具，为与ERβ和HDACs相关疾病的诊疗研究带来新的见解。
